Association of ITPA gene variation and serum ribavirin concentration with a decline in blood cell concentrations during pegylated interferon-alpha plus ribavirin therapy for chronic hepatitis C

Mina Nakagawa; Naoya Sakamoto; Takako Watanabe; Yuki Nishimura-Sakurai; Izumi Onozuka; Seishin Azuma; Sei Kakinuma; Sayuri Nitta; Kei Kiyohashi; Akiko Kusano-Kitazume; Miyako Murakawa; Kohei Yoshino; Yasuhiro Itsui; Yasuhito Tanaka; Masashi Mizokami; Mamoru Watanabe; Ochanomizu-Liver Conference Study Group

doi:10.1007/s12072-012-9363-6

Association of ITPA gene variation and serum ribavirin concentration with a decline in blood cell concentrations during pegylated interferon-alpha plus ribavirin therapy for chronic hepatitis C

Hepatol Int. 2013 Mar;7(1):153-61. doi: 10.1007/s12072-012-9363-6. Epub 2012 Mar 21.

Authors

Mina Nakagawa^{1

2}, Naoya Sakamoto^{3

4

5}, Takako Watanabe¹, Yuki Nishimura-Sakurai¹, Izumi Onozuka¹, Seishin Azuma¹, Sei Kakinuma^{1

2}, Sayuri Nitta¹, Kei Kiyohashi¹, Akiko Kusano-Kitazume¹, Miyako Murakawa¹, Kohei Yoshino¹, Yasuhiro Itsui⁶, Yasuhito Tanaka⁷, Masashi Mizokami⁸, Mamoru Watanabe¹; Ochanomizu-Liver Conference Study Group

Affiliations

¹ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
² Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.
³ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. nsakamoto.gast@tmd.ac.jp.
⁴ Department of Gastroenterology and Hepatology, Graduate School of Medicine Hokkaido University, Sapporo, Japan. nsakamoto.gast@tmd.ac.jp.
⁵ Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan. nsakamoto.gast@tmd.ac.jp.
⁶ Department of Internal Medicine, Soka Municipal Hospital, Saitama, Japan.
⁷ Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁸ Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

PMID: 26201629
DOI: 10.1007/s12072-012-9363-6

Abstract

Background: Genetic variation leading to inosine triphosphatase (ITPA) deficiency protects chronic hepatitis C patients receiving ribavirin against hemolytic anemia. The relationship between ITPA gene variation and serum ribavirin concentration was analyzed in association with a reduction in blood cells and dose reduction of pegylated interferon (PEG-IFN) or ribavirin.

Patients and methods: A total of 300 hepatitis C patients treated with PEG-IFN plus ribavirin were analyzed. Genetic polymorphisms were determined in ITPA and the quantitative reduction in blood cells from the baseline was analyzed every 4 weeks for the duration of treatment and after the end of therapy. The decline in hemoglobin (Hb) or platelet (PLT) level at week 4 compared to baseline was also assessed according to ribavirin concentrations.

Results: Patients with the ITPA-CA/AA genotypes showed a lower degree of Hb reduction throughout therapy than those with the ITPA-CC genotype and a marked difference in mean Hb reduction was found at week 4 (CA/AA -1.0 vs. CC -2.8, p < 0.001). The ITPA-CC genotype had significantly less reduction in the mean platelet count than the ITPA-CA/AA genotypes early during treatment (p < 0.001 for weeks 4 and 8). Patients with the ITPA-CA/AA genotypes were less likely to develop anemia, regardless of the concentration of ribavirin. Patients with baseline PLT counts below 130 × 10(3)/μl had a significantly lower tendency to achieve sustained virological response (SVR), especially those with the ITPA-CA/AA genotypes. ITPA gene variation was not extracted by multivariable analysis as an important predictor of SVR.

Conclusions: Despite the fact that ITPA variants were less likely to develop anemia, patients with low baseline PLT counts were difficult to treat, especially those with the ITPA-CA/AA genotype. These results may give a valuable pharmacogenetic diagnostic tool for the tailoring of dosing to minimize drug-induced adverse events.

Keywords: Hepatitis C virus (HCV); ITPA (inosine triphosphatase); Pegylated interferon plus ribavirin therapy.